The present invention relates generally to the mass spectroscopic analysis of chemical samples and more particularly to time-of-flight mass spectrometry. A means and method are described for the analysis of ionized species in a spectrometer comprising two or more reflecting devices such that ions can be reflected back and forth a plurality of times therebetween.
The present invention relates in general to ion beam handling in mass spectrometers and more particularly to a means of focusing ions in time-of-flight mass spectrometers (TOFMS). The apparatus and method of mass analysis described herein is an enhancement of the techniques that are referred to in the literature relating to mass spectrometry.
The analysis of ions by mass spectrometers is important, as mass spectrometers are instruments that are used to determine the chemical structures of molecules. In these instruments, molecules become positively or negatively charged in an ionization source and the masses of the resultant ions are determined in vacuum by a mass analyzer that measures their mass/charge (m/q) ratio. Mass analyzers come in a variety of types, including magnetic field (B), combined (double-focusing) electrical (E) and magnetic field (B), quadrupole (Q), ion cyclotron resonance (ICR), quadrupole ion storage trap, and time-of-flight (TOF) mass analyzers, which are of particular importance with respect to the invention disclosed herein. Each mass spectrometric method has a unique set of attributes. Thus, TOFMS is one mass spectrometric method that arose out of the evolution of the larger field of mass spectrometry.
The analysis of ions by TOFMS is, as the name suggests, based on the measurement of the flight times of ions from an initial position to a final position. Ions which have the same initial kinetic energy but different masses will separate when allowed to drift through a field free region.
Ions are conventionally extracted from an ion source in small packets. The ions acquire different velocities according to the mass-to-charge ratio of the ions. Lighter ions will arrive at a detector prior to high mass ions. Determining the time-of-flight of the ions across a propagation path permits the determination of the masses of different ions. The propagation path may be circular or helical, as in cyclotron resonance spectrometry, but typically linear propagation paths are used for TOFMS applications.
TOFMS is used to form a mass spectrum for ions contained in a sample of interest. Conventionally, the sample is divided into packets of ions that are launched along the propagation path using a pulse-and-wait approach. In releasing packets, one concern is that the lighter and faster ions of a trailing packet will pass the heavier and slower ions of a preceding packet. Using the traditional pulse-and-wait approach, the release of an ion packet as timed to ensure that the ions of a preceding packet reach the detector before any overlap can occur. Thus, the periods between packets is relatively long. If ions are being generated continuously, only a small percentage of the ions undergo detection. A significant amount of sample material is thereby wasted. The loss in efficiency and sensitivity can be reduced by storing ions that are generated between the launching of individual packets, but the storage approach carries some disadvantages.
Resolution is an important consideration in the design and operation of a mass spectrometer for ion analysis. The traditional pulse-and-wait approach in releasing packets of ions enables resolution of ions of different masses by separating the ions into discernible groups. However, other factors are also involved in determining the resolution of a mass spectrometry system. xe2x80x9cSpace resolutionxe2x80x9d is the ability of the system to resolve ions of different masses despite an initial spatial position distribution within an ion source from which the packets are extracted. Differences in starting position will affect the time required for traversing a propagation path. xe2x80x9cEnergy resolutionxe2x80x9d is the ability of the system to resolve ions of different mass despite an initial velocity distribution. Different starting velocities will affect the time required for traversing the propagation path.
In addition, two or more mass analyzers may be combined in a single instrument to form a tandem mass spectrometer (MS/MS, MS/MS/MS, etc.). The most common MS/MS instruments are four sector instruments (EBEB or BEEB), triple quadrupoles (QQQ), and hybrid instruments (EBQQ or BEQQ). The mass/charge ratio measured for a molecular ion is used to determine the molecular weight of a compound. In addition, molecular ions may dissociate at specific chemical bonds to form fragment ions. Mass/charge ratios of these fragment ions are used to elucidate the chemical structure of the molecule. Tandem mass spectrometers have a particular advantage for structural analysis in that the first mass analyzer (MS1) can be used to measure and select molecular ion from a mixture of molecules, while the second mass analyzer (MS2) can be used to record the structural fragments. In tandem instruments, a means is provided to induce fragmentation in the region between the two mass analyzers. The most common method employs a collision chamber filled with an inert gas, and is known as collision induced dissociation CID. Such collisions can be carried out at high (5-10 keV) or low (10-100 eV) kinetic energies, or may involve specific chemical (ion-molecule) reactions. Fragmentation may also be induced using laser beams (photodissociation), electron beams (electron induced dissociation), or through collisions with surfaces (surface induced dissociation). It is possible to perform such an analysis using a variety of types of mass analyzers including TOF mass analysis.
In a TOFMS instrument, molecular and fragment ions formed in the source are accelerated to a kinetic energy:
qV=xc2xd mv2xe2x80x83xe2x80x83(1)
where q is the elemental charge, V is the potential across the source/accelerating region, m is the ion mass, and v is the ion velocity. These ions pass through a field-free drift region of length L with velocities given by equation 1. The time required for a particular ion to traverse the drift region is directly proportional to the square root of the mass/charge ratio:
t=L(m/2qV)xc2xdxe2x80x83xe2x80x83(2)
Conversely, the mass/charge ratios of ions can be determined from their flight times according to the equation:
m/e=xcex1t2+xcex2xe2x80x83xe2x80x83(3)
where xcex1 and xcex2 are constants which can be determined experimentally from the flight times of two or more ions of known mass/charge ratios.
Generally, TOF mass spectrometers have limited mass resolution. This arises because there may be uncertainties in the time that the ions were formed (time distribution), in their location in the accelerating field at the time they were formed (spatial distribution), and in their initial kinetic energy distributions prior to acceleration (energy distribution).
The first commercially successful TOFMS was based on an instrument described by Wiley and McLaren in 1955 (Wiley, W. C.; McLaren, I. H., Rev. Sci. Instrumen. 26 1150 (1955)). That instrument utilized electron impact (EI) ionization (which is limited to volatile samples) and a method for spatial and energy focusing known as time-lag focusing. The simplest form of the Wiley-McLaren instrument is depicted in FIG. 1. The instrument consists, in part, of an ion accelerator, a detector, and a field free drift region between the accelerator and the detector. At the beginning of an analysis, ions are located in the accelerator near plane P1xe2x80x94the xe2x80x9cobject planexe2x80x9d. The ions initially have near thermal kinetic energies. To begin the analysis, an electrical potential is applied to the accelerator. The electric field in the accelerator accelerates ions toward a detector which resides at plane P2xe2x80x94the xe2x80x9cimage planexe2x80x9d. For the purpose of the present discussion, it is assumed that ions are accelerated in a single region of the accelerator and that the electric field strength is uniform throughout this region.
As was first derived by Wiley and Maclaren, ions of a given mass-to-charge ratio (m/q) starting at a variety of positions near the object plane will all arrive at the image plane at substantially the same time. This effect is referred to by Wiley and Maclaren as xe2x80x9cspace focusingxe2x80x9d. Notice that if s is the distance between the object plane, P1, and the end of the accelerator, then D, the distance between the image plane, P2, and the end of the accelerator, will be equal to 2s. Placing the detector at the image plane will result in the optimal space focusing and therefore the highest mass resolution.
Wiley and Maclaren also described the use of two consecutive acceleration regions whereby an image plane may be formed farther from the accelerator and therefore provide higher mass resolution. It is this xe2x80x9ctwo stagexe2x80x9d acceleration instrument that was commercialized. In the commercialized instrument, molecules are first ionized by a pulsed (1-5 microsecond) electron beam. Spatial focusing was accomplished using two stages of ion acceleration. In the first stage, a low voltage (xe2x88x92150 V) drawout pulse is applied to the source region that compensates for ions formed at different locations, while the second stage completes the acceleration of the ions to their final kinetic energy (xe2x88x923 keV ). A short time-delay (1-7 microseconds) between the ionization and drawout pulses compensates for different initial kinetic energies of the ions, and is designed to improve mass resolution. Because this method required a very fast (40 ns) rise time pulse in the source region, it was convenient to place the ion source at ground potential, while the drift region floats at xe2x88x923 kV. The instrument was commercialized by Bendix Corporation as the model NA-2, and later by CVC Products (Rochester, N.Y.) as the model CVC-2000 mass spectrometer. The instrument has a practical mass range of 400 daltons and a mass resolution of 1/300, and is still commercially available.
There have been a number of variations on this instrument. Muga (TOFTEC, Gainsville) has described a velocity compaction technique for improving the mass resolution (Muga velocity compaction). Chatfield et al. (Chatfield FT-TOF) described a method for frequency modulation of gates placed at either end of the flight tube, and Fourier transformation to the time domain to obtain mass spectra. This method was designed to improve the duty cycle.
Cotter et al. (VanBreeman, R. B.: Snow, M.: Cotter, R. J., Int. J. Mass Spectrom. Ion Phys. 49 (1983) 35.; Tabet, J. C.; Cotter, R. J., Anal. Chem. 56 (1984) 1662; Olthoff, J. K.; Lys, I.: Demirev, P.: Cotter, R. J., Anal. Instrumen. 16 (1987) 93) modified a CVC 2000 time-of-flight mass spectrometer for infrared laser desorption of involatile biomolecules, using a Tachisto (Needham, Mass.) model 215G pulsed carbon dioxide laser. This group also constructed a pulsed liquid secondary time-of-flight mass spectrometer (liquid SIMS-TOF) utilizing a pulsed (1-5 microsecond) beam of 5 keV cesium ions, a liquid sample matrix, a symmetric push/pull arrangement for pulsed ion extraction (Olthoff, J. K.; Cotter, R. J., Anal. Chem. 59 (1987) 999-1002.; Olthoff, J. K.; Cotter, R. J., Nucl. Instrum. Meth. Phys. Res. B-26 (1987) 566-570. In both of these instruments, the time delay range between ion formation and extraction was extended to 5-50 microseconds, and was used to permit metastable fragmentation of large molecules prior to extraction from the source. This in turn reveals more structural information in the mass spectra.
The plasma desorption technique introduced by Macfarlane and Torgerson in 1974 (Macfarlane, R. D.; Skowronski, R. P.; Torgerson, D. F., Biochem. Biophys. Res Commoun. 60 (1974) 616.) formed ions on a planar surface placed at a voltage of 20 kV. Since there are no spatial uncertainties, ions are accelerated promptly to their final kinetic energies toward a parallel, grounded extraction grid, and then travel through a grounded drift region. High voltages are used, since mass resolution is proportional to Uo/eV, where the initial kinetic energy, Uo is of the order of a few electron volts. Plasma desorption mass spectrometers have been constructed at Rockefeller (Chait, B. T.; Field, F. H., J. Amer. Chem. Soc. 106 (1984) 193), Orsay (LeBeyec, Y.; Della Negra, S.; Deprun, C.; Vigny, P.; Giont, Y. M., Rev. Phys. Appl. 15 (1980) 1631), Paris (Viari, A.; Ballini, J. P.; Vigny, P.; Shire, D.; Dousset, P., Biomed. Environ. Mass Spectrom, 14 (1987) 83), Upsalla (Hakansson, P.; Sundqvist B., Radiat. Eff. 61 (1982) 179) and Darmstadt (Becker, O.; Furstenau, N.; Krueger, F. R.; Weiss, G.; Wein, K., Nucl. Instrum. Methods 139 (1976) 195). A plasma desorption time-of-flight mass spectrometer has been commercialized by BIO-ION Nordic (Upsalla, Sweden). Plasma desorption utilizes primary ion particles with kinetic energies in the MeV range to induce desorption/ionization. A similar instrument was constructed at Manitobe (Chain, B. T.; Standing, K. G., Int. J. Mass Spectrum. Ion Phys. 40 (1981) 185) using primary ions in the keV range, but has not been commercialized.
Matrix-assisted laser desorption, introduced by Tanaka et al. (Tanaka, K.; Waki, H.; Ido, Y.; Akita, S.; Yoshida, Y.; Yoshica, T., Rapid Commun. Mass Spectrom. 2 (1988) 151) and by Karas and Hillenkamp (Karas, M.; Hillenkamp, F., Anal. Chem. 60 (1988) 2299) utilizes TOFMS to measure the molecular weights of proteins in excess of 100,000 daltons. An instrument constructed at Rockefeller (Beavis, R. C.; Chait, B. T., Rapid Commun. Mass Spectrom. 3 (1989) 233) has been commercialized by VESTEC (Houston, Tex.), and employs prompt two-stage extraction of ions to an energy of 30 keV.
Time-of-flight instruments with a constant extraction field have also been utilized with multi-photon ionization, using short pulse lasers.
The instruments described thus far are linear time-of-flight spectrometers. That is, there is no additional focusing after the ions are accelerated and allowed to enter the drift region. Two approaches to additional energy focusing have been utilized: those which pass the ion beam through an electrostatic energy filter and those which use an ion mirror.
The reflectron (or ion mirror) was first described by Mamyrin (Mamyrin, B. A.; Karatajev. V. J.; Shmikk, D. V.; Zagulin, V. A., sov. Phys., JETP 37 (1973) 45). As depicted in FIG. 2, the operation of the reflectron is in effect the same as that of the ion accelerator discussed above. Ions are assumed to start at an object or image plane located at P2. Ions are assumed to start at plane P2 having already been accelerated to their full kinetic energy and moving toward the reflectron. After having traveled some distance, D2, in a field free region, the ions enter the reflectron. The electrostatic field within the energized reflectron slows the ions to a stop at a distance s from the entrance of the reflectron. Ions are then re-accelerated toward image plane P3 and to their original kinetic energy by the reflectron""s electrostatic field. After exiting the reflectron, the ions travel a distance D2 to image plane P3. Within a certain kinetic energy range, all ions of a given m/q, having started at plane P2 simultaneously, will arrive at image plane P3 at substantially the same time. Improved mass resolution results from the fact that ions with larger kinetic energies must penetrate the reflecting field more deeply before being turned around. These faster ions then catch up with the slower ions at the detector and are thus temporally focused.
For the purpose of the present discussion, it is assumed that ions are accelerated in a single region of the reflectron and that the electric field strength is uniform throughout this region. In such a case, the relationship between D1, D2, and s is given by:
D1+D2=4sxe2x80x83xe2x80x83(4)
If D1=D2=D then as in the discussion of the Wiley-Maclaren accelerator above, D=2s.
As with the Wiley-Maclaren accelerator, the reflectron might consist of more than one acceleration xe2x80x9cstagexe2x80x9d. Such multistage reflectrons have been discussed extensively in the technical literature. See, for example, U. Boesl, R. Weinkauf, and E. W. Schlag, Int. J. Mass Spectrom. Ion Process., 112, 121(1992). Multistage reflectrons have the advantage that they can temporally focus ions of a broader range of kinetic energies.
The Wiley-Maclaren accelerator and Mamyrin reflectron may be combined in a single instrument as depicted in FIG. 3. Here, ions start at object plane, P1, in a single stage accelerator. The ions are accelerated and space focused to image plane, P2. As discussed with respect to FIG. 1, due to space focusing all ions of a given m/q pass through plane P2 at substantially the same time. From this point, the distribution of ion kinetic energies would result in a temporal defocusing of the ions and a loss in mass resolution. However, image plane P2 may be treated as the starting point for ions passing through the reflectron. As discussed with respect to FIG. 2, the reflectron can focus ions from image plane P2 to image plane P3. If a detector is placed at P3 then all ions of a given m/q will be temporally focused so that they arrive at the detector at substantially the same time and will thereby provide the optimum mass resolution.
Reflectrons were used on the laser microprobe instrument introduced by Hillenkamp et al. (Hillenkamp, F.; Kaufmann, R.; Nitsche, R.; Unsold, E., Appl. Phys. 8 (1975) 341) and commercialized by Leybold Hereaus as the LAMMA (LAser Microprobe Mass Analyzer). A similar instrument was also commercialized by Cambridge Instruments as the IA (Laser Ionization Mass go Analyzer). Benninghoven (Benninghoven reflectron) has described a SIMS (secondary ion mass spectrometer) instrument that also utilizes a reflectron, and is currently being commercialized by Leybold Hereaus. A reflecting SIMS instrument has also been constructed by Standing (Standing, K. G.; Beavis, R.; Bollbach, G.; Ens, W.; Lafortune, F.; Main, D.; Schueler, B.; Tang, X.; Westmore, J. B., Anal. Instrumen. 16 (1987) 173).
Lebeyec (Della-Negra, S.; Lebeyec, Y., in Ion Formation from Organic Solids IFOS III, ed. by A. Benninghoven, pp 42-45, Springer-Verlag, Berlin (1986)) described a coaxial reflectron time-of-flight mass spectrometer that reflects ions along the same path in the drift tube as the incoming ions, and records their arrival times on a channelplate detector with a centered hole that allows passage of the initial (unreflected) beam. This geometry was also utilized by Tanaka et al. (Tanaka, K.; Waki, H.; Ido, Y.; Akita, S.; Yoshida, T., Rapid Comun. Mass Spectrom. 2 (1988) 151) for matrix assisted laser desorption. Schlag et al. (Grotemeyer, J.; Schlag, E. W., Org. Mass Spectrom. 22 (1987) 758) have used a reflectron on a two-laser instrument. The first laser is used to ablate solid samples, while the second laser forms ions by multiphoton ionization. This instrument is currently available from Bruker. Wollnik et al. (Grix., R.; Kutscher, R.; Li, G.; Gruner, U.; Wollnik, H., Rapid Commun. Mass Spectrom. 2 (1988) 83) have described the use of reflectrons in combination with pulsed ion extraction, and achieved mass resolutions as high as 20,000 for small ions produced by electron impact ionization.
A dual-reflectron time-of-flight mass spectrometer has been previously described by Cotter et al. (Cotter, R. J. and Cornish, T. J.; U.S. Pat. No. 5,202,563 and Cornish, T. J., and Cotter, R. J., Time of Flight Mass Spectrometry, R. J. Cotter ed., American Chemical Society, Washington, D.C., 1994). The instrument described comprises an ion source wherein ions are generated and then accelerated towards a first reflectron. An electrostatic field generated by the energized reflectron reflects ions towards a second reflectron. Similarly, the second reflectron reflects ions toward an ion detector. Cotter et al. demonstrated that in one particular instance the mass resolving power of the spectrometer observed when using the instrument as described above is about double that observed when using only a single reflectron. Notably, however, the spectrometer described by Cotter et al. is limited to two reflections as only two reflectrons are used and these are positioned so that ions follow a Z shaped trajectory through the instrument. Also, notable is the fact that neither of the reflectrons can be pulsed on or off in a microsecond time frame.
Additionally, Mamyrin et al. U.S. Pat. No. 4,072,862 discloses a time-of-flight mass spectrometer whose analyzer chamber accommodates a pulsed ion source, an ion detector and an ion reflecting system, all disposed on one and the same ion optical axis. Mamyrin""s prior art spectrometer is his depicted in FIG. 4. Parts of the spectrometer according to the present invention resemble this arrangement superficially, however, as will be seen below, the present invention has some significant differences with regard to both means and method. Notice in the case of Mamyrin that ions are generated in a source which is integrated into the mass analyzer. The ion detector and the ion reflecting system described in Mamyrin et al. are disposed on opposite sides of the ion source that is composed of electrodes which are transparent to the ions being studied. Ions generated are accelerated out of this ion source along the axis of the analyzer via electric potentials on two or three metal planar electrodes. The ions are then reflected by a reflectron back towards the ion source. According to Mamyrin, by the time the ions arrive back at the source, the source electrodes are deenergized so that the ions can pass through the source and into the detector. However, the ion source of Mamyrin et al. is not designed in such a way as to be useful as a reflectron or reflecting device. Furthermore, Mamyrin et al. neither teach nor no suggest any method of ion analysis via multiple passes through reflecting devices.
It has been suggested by Wollnik, H., in Time-of-flight Mass Analyzers, Mass Spec. Rev., 1993, 12, p.109, that two reflectrons may be configured coaxially with respect to one another in such a way that ions can be reflected back and forth between them. Wollnik""s prior art spectrometer is depicted in FIG. 5. (see also, Wollnik et al., Spectral Analysis Based on Bipolar Time-Domain Sampling: A Multiplex Method for Time-of-Flight Mass Spectrometry, Anal. Chem., 1992, 64, p.1601, and Herman Wollnik, UK Patent Application No. 8120809 and German Patent No. 3025764). Parts of the spectrometer according to the present invention resemble this arrangement superficially, however, as will be seen below, the present invention has some significant differences with regard to both the apparatus and method.
In the hypothetical instrument as shown in FIG. 5, Wollnik suggests that two reflectrons 50, 52 be placed coaxially with respect to one another, that an ion source 54 be placed at one end of the instrument, and that a detector 56 be placed at the other end. The ion source 54 is used to generate analyte ions in a pulsed manner. The ions are accelerated to their full analysis velocity by the ion source 54. That is, the sum of the kinetic and potential energies of the ions does not change significantly 10o between the time the ions exit the ion source 54 and the end of 1al the mass analysis. Ions exit the ion source 54 fully accelerated and pass through the reflectron 50 (the first reflectron) immediately adjacent to the ion source 54xe2x80x94which at the time is at ground potential.
After the ions have pass through reflectron 50, reflectron 50 is rapidly energized to a high potential. In contrast, reflectron 52, adjacent to the detector 56, is energized before and during the analysis. While both reflectrons 50, 52 are energized, ions are repeatedly reflected back and forth between them (as indicated by ion path 58). To conclude the analysis, reflectron 52 must be rapidly deenergized to ground potential so that ions are then able to pass through it and into the detector 56. However, Wollnik does not teach how a reflectron or similar device might be pulsed xe2x80x9cONxe2x80x9d or xe2x80x9cOFFxe2x80x9d.
Notice again that in Wollnik""s prior art spectrometer, the reflectron is not used to accelerate ions to their analysis energy. Rather, Wollnik teaches the use of the ion source 54 to accelerate the ions. This is because Wollnik""s reflectron 50 is inadequate for accelerating ions to their analysis energy but is adequate only for reflecting ions.
Consider, for example, the use of a two stage reflectron as an accelerator in a one meter spectrometer according to Wollnik""s design as depicted in FIG. 5. In such a case the image plane would be about 0.5 m from the reflectron. Using equation 3 of Schlag et al. (Int J Mass Spectrom. Ion Process., 112, 121(1992)) one can determine the minimum dimensions and potentials applied to the reflectron. The minimum length of the reflectron would be about 7 cm. The xe2x80x9cfrontxe2x80x9d stage would be about 1 cm long (XA2=0.01 m in Schlag""s notation) and the xe2x80x9cbackxe2x80x9d stage would be about 6 cm long. Assuming the ions are to have a analysis kinetic energy of about 6.75 kV, and the starting position within the reflectron to be about 0.047 m from the grid separating the two accelerating stages (i.e. XA1=0.047 m), then, the potential applied to the grid separating the two accelerating stages would be UA2xcx9c4.59 kV and the potential applied to the back of the reflectron would be 7.332 kV so that the potential at the starting position would be U=6.75 kV. Under such circumstances, accelerating leu-enkephalin ions from rest at XA1=0.047 m would result in a flight time of the ions to the image plane of about 14.5 microseconds. More importantly, the flight time distribution would be largexe2x80x94about 12 ns or more. This is by far the largest error in the measurement and would have a substantial negative impact on the resolution of the spectrometer. Indeed Schlag et al. indicate that such a device is not useful as an accelerator because xe2x80x9cthe electric field in the first stage of the [accelerator] has to be very weak, which induces a large spread in flight times, e.g. due to the xe2x80x98turn around timexe2x80x99 effect.xe2x80x9d
Also note that Wollnik does not teach how the reflectron may be pulsed rapidly to high voltage from ground or vice versa. This is an important consideration in the construction of his proposed analyzer. Assuming, for example, the flight time of ions from one reflectron to the other is about 30 xcexcsec, then all of the electrodes of reflectron 1 must be pulsed to the appropriate high voltages in a substantially shorter time than thisxe2x80x94e.g. 1 xcexcsec. Also, all the electrodes of reflectron 2 must be pulsed to ground in a short time frame in order to conclude the analysis. Although one might in theory control the potential on each and every electrode of both reflectrons with its own individual pulser, such would prove impractical and costly.
Finally, notice in Wollnik""s spectrometer of FIG. 5, that the instrument is limited in the ion sources that might be used with the analyzer. The only ion sources that can be used are those external to the analyzer, that produce ions in a pulsed manner (typically nanoseconds in duration), and produce ions that are already at their analysis energy when they exit the source.
The performance of the instrument is directly influenced by the duration of the ion pulses produced by the source. That is, the pulse of ions finally observed at the detector cannot be shorter in duration than the duration of the ion pulse produced at the source. As the mass resolving power of the instrument is inversely proportional to the ion pulse duration at the detector, it is clear that the duration of the ion pulse produced at the source is of critical importance in the performance of the instrument as a whole. Also, the signal-to-noise ratio and therefore the limit of detection of the instrument is related to the width of the ion pulse. Broader pulses will result in a lower signal-to-noise ratio and a lower limit of detection.
The purpose of the present invention is to provide a means and method for operating a device which can serve as an accelerator and a reflectron in a TOF mass spectrometer and which can also be energized and deenergized in a pulsed manner. It is a further purpose of the present invention to provide a means and method of operating a mass spectrometer which uses said device to accept ions from a source which is either external or internal to the analyzer and analyze them in a TOF mass analyzer wherein ions are reflected multiple times between said device and one or more reflectrons for the purpose of improving the mass resolution of the instrument. It is a further purpose of the present invention to provide a means and method of operating a mass spectrometer the resolution of which is substantially not influenced by the duration of the ion pulse produced by the ion source and wherein ions are reflected multiple times between one or more reflecting devices for the purpose of improving the mass resolution of the instrument.
Several references relate to the technology herein disclosed. For example, F. Hillenkamp, M. Karas, R. C. Beavis, B. T. Chait, Anal. Chem. 63(24), 1193A(1991); Wei Hang, Pengyuan Yag, Xiaoru Wang, Chenglong Yang, Yongxuan Su, and Benli Huang, Rapid Comm. Mass Spectrom. 8, 590(1994); A. N. Verentchikov, W. Ens, K. G. Standing, Anal. Chem. 66, 126(1994); J. H. J. Dawson, M. Guilhaus, Rapid Comm. Mass Spectrom. 3, 155(1989); M. Guilhaus, J. Am. Soc. Mass Spectrom. 5, 588(1994); E. Axelsson, L. Holmlid, Int. J. Mass Spectrom. Ion Process. 59, 231(1984); O. A. Mirgorodskaya, et al., Anal. Chem. 66, 99(1994); S. M. Michael, B. M. Chien, D. M. Lubman, Anal. Chem. 65, 2614(1993); W. C. Wiley, I. H. McLaren, Rev. Sci. Inst. 26(12), 1150(1955).
The present invention relates generally to time-of-flight mass spectrometers. More specifically, the invention comprises an improved method and apparatus for analyzing ions using a time-of-flight mass spectrometer. In the present invention, two or more ion reflecting devices are positioned with respect to one another such that ions generated by an ion source can be reflected back and forth between them.
The first reflecting device is an ion accelerator whose function is two-fold. First, it acts as an accelerating device and provides the initial acceleration to ions received from the ion source. Second, the accelerator acts as a reflecting device and reflects the ions in the subsequent mass analysis. As discussed above and in reference to the prior art work of Mamyrin and Wollnik, the ability of the accelerator according to the present invention to act both to accelerate the ions and reflect them in the subsequent analysis is an important feature of the instrument according to the present invention.
The second reflecting device is a reflectron and acts only to reflect ions in such a manner that all ions of a given mass-to-charge ratio have substantially the same flight time through the analyzer. During ion analysis, ions are reflected back and forth between the accelerator and reflectron(s) multiple times. At the end of the ion analysis, the accelerator is rapidly deenergized so as to allow the ions to pass through the accelerator and subsequently into a detector. Alternatively, the reflectron is rapidly deenergized so as to allow the ions to pass through the reflectron and subsequently into a detector. Alternatively, the analysis may be concluded by deflecting the ions into a detector using electrostatic deflection plates or one of the reflectrons might be rapidly deenergized so as to allow ions to pass through it and into a detector located behind it. Importantly, the elements of the accelerator and/or reflectron(s) are energized and deenergized in a pulsed manner via a resistor-capacitor (RC) divider specifically designed for this purpose.
By reflecting the analyte ions back and forth between the accelerator and the reflectron several times, a much longer flight path can be achieved in a given size spectrometer than could otherwise be achieved. Consequently, the mass resolving power of the TOF mass spectrometer taught here can be substantially greater than could otherwise be achieved in a TOF mass spectrometer of similar size.
Notice that because the present invention uses a specially designed accelerator, the present invention does not require and does not use an ion source which generates high kinetic energy ions in a pulsed manner. Rather, the present invention can employ a variety of ion sources that produce relatively low kinetic energy ions. The ion source according to the present invention may be either internal or external to the accelerator. Also, ions can be injected into the accelerator in either a pulsed, continuous, or semi-continuous manner. In contrast to Wollnik""s prior art, the performance of the present invention in terms of mass resolving power is not substantially influenced by the width of the ion pulse produced by the ion source. Rather, the analysis of the ions is initiated when the accelerator is pulsed xe2x80x9cONxe2x80x9d. That is, the pulsing of the accelerator forms the ions into a well defined ion pulse. By pulsing the accelerator xe2x80x9cONxe2x80x9d for about 100 ns, the ions can be formed into a pulse which is on the order of a 2ns duration regardless of the duration of the ion pulse provided by the source.
Other objects, features, and characteristics of the present invention, as well as the methods of operation and functions of the related elements of the structure, and the combination of parts and economies of manufacture, will become more apparent upon consideration of the following detailed description with reference to the accompanying drawings, all of which form a part of this specification.